Defective Homocysteine Metabolism: Potential Implications for Skeletal Muscle Malfunction

Abstract

Hyperhomocysteinemia (HHcy) is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy) metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular methylation and cellular antioxidant potential and imbalances in Hcy production and/or catabolism impacts gene expression and cell signaling including GPCR signaling. Furthermore, HHcy might damage the vagus nerve and superior cervical ganglion and affects various GPCR functions; therefore it can impair both the parasympathetic and sympathetic regulation in the blood vessels of skeletal muscle and affect long-term muscle function. Understanding cellular targets of Hcy during HHcy in different contexts and its role either as a primary risk factor or as an aggravator of certain disease conditions would provide better interventions. In this review we have provided recent Hcy mediated mechanistic insights into different diseases and presented potential implications in the context of reduced muscle function and integrity. Overall, the impact of HHcy in various skeletal muscle malfunctions is underappreciated; future studies in this area will provide deeper insights and improve our understanding of the association between HHcy and diminished physical function.

Hyperhomocysteinemia inhibits satellite cell regenerative capacity through p38 alpha/beta MAPK signaling

“…Although it needs to be further established in the case of human scenario with the HHcy condition, our study identified several similarities that indicate compromised satellite cell function in humans as well. 1) Association between HHcy and muscle weakness was reported both in the humans and in mouse models (24,26). 2) HHcy was associated with progressive decline in body weights both in humans and in mouse models (12,14,29).…”

“…Several of the age-induced changes in skeletal muscles such as reduced body weight and muscle weakness were also reported during hyperhomocysteinemia (HHcy), a metabolic condition that results from accumulation of the noncoding intermediary amino acid, homocysteine (Hcy), due to defective metabolism (24). Furthermore, HHcy was reported to aggravate elderly frailty (24).…”

“…Furthermore, HHcy was reported to aggravate elderly frailty (24). Earlier studies reported that children born with severe HHcy condition, which often results in homocystinuria, exhibited lower than normal body weights (12).…”

Relationship between Homocysteine and Muscle Strength Decline: The Baltimore Longitudinal Study of Aging

“…(6) Homocysteine also decreases the bioavailability of nitric oxide, which regulates blood flow to muscle cells; this can lead to a reduction in endurance, greater fatigue, muscular dystrophy, and ischemia. (6) A c c e p t e d M a n u s c r i p t…”

“…(5) Homocysteine is a sulfur-containing amino acid metabolized in both the remethylation and transulfuration metabolic pathways. Elevated homocysteine concentrations are a known risk factor for vascular disease (6,7) and have been associated with fractures, disability, frailty, slow gait speed, poor balance, and poor physical function. (7,8,9) There is no standard cut point for elevated homocysteine concentrations but high homocysteine is frequently defined as >13 μmol/L(10) and the prevalence of high homocysteine among adults aged 60 years and older is nearly 20%.…”